Development, Function, and TraffickingNK cells are derived from both the common lymphoid progenitor (CLP) and the early thymocyte progenitor (ETP) cells, but unlike T cells do not require the thymus for development (see (a) under Small Mature Lymphocyte). In congenitally athymic individuals (DiGeorge Syndrome), NK cell development is normal but T cell development is markedly impaired. In children and adults, early NK cell development occurs in the bone marrow, but further development probably occurs in some peripheral sites. NK precursor (NKP) and immature NK (iNK) cells are found in the liver and spleen. Mature NK (mNK) cells are found in the bone marrow, spleen, liver, lymph nodes, and the uterus, especially during gestation. They are present only in small numbers or not at all in the G-I tract, skin, muscle, and brain. Increased numbers are found in the peripheral blood in asplenic individuals and during the later stages of pregnancy. mNK cells in peripheral tissue sites require Il-15 signaling with stromal and DCs for survival. Some mNK cells are long lived, and the bone marrow may provide a niche for longevity, much the way it does for long lived plasma cells. NK cells were first recognized as a result of their ability to lyse certain tumor cells without prior sensitivation, an innate immune response. One well described mechanism is through the CD16a receptor which recognizes the FcγIIIR receptor of antibodies coating the target cells. This process is referred to as antibody-dependent cellular cytotoxicity (ADCC). They also lyse cells infected with viruses and other microorganisms through the same mechanism. The main mechanism for target cell killing, is through exocytosis of perforin and granzyme B from cytoplasmic granules resulting in target cell lysis, a process similar to complement-induced cell lysis. This cytotoxicity mechanism is associated more with the CD16a (low) than with the CD16a (high) subset. They also can kill target cells via the FasL- and TRAIL- mediated pathways. Finally, NK cells of the CD56 (bright), CD16a (negative) subset secrete several cytokines, e.g. INF-γ, TNF-α, GM-CSF, and chemokines (e.g. MIP-1α) that amplify the adaptive immune and inflammatory response in general. NK cells are normally under both inhibitory and activatory control to prevent lysis of normal self cells, and yet participate in an immune response when necessary. A group of cell surface structures referred to as killer immunoglobulin-like receptors (KIRs), some 15 members in all, that bind to MHC class 1 structures on normal and target cells play an important role in maintaining this balance. Members of the KIR L family bind to the classical MHC-1 molecule, HLA-C, and inhibit NK cells. Another surface structure, CD94/NKG2A that binds to the non-classical MHC-1 molecule, HLA-E, also inhibits NK cells. Both of these interactions blunt the signaling pathways via activation of SHP-1 and SHP-2 tyrosine phosphatases. Activation receptors such as those of the KIR S family and CD94/NKG2C that bind to altered classical MHC-1 molecules, HLA-1 and HLA-E respectively result in activation via DAP10, DAP12, and SAP/Fyn adaptors. The expression of some of these molecules on the surface of the NK cells is dependent to some extent on the sites in which the NK cells reside, e.g. CD56 (bright); peripheral blood NK cells do not express KIRs. NKT cells- Another immunophenotypically distinctive subset of NK cells that express both NK and T cell markers including the TCR are referred to as TNK cells. Unlike NK cells they develop in the thymus from cortical thymocytes (T cells) that coexpress CD4 and CD8 (double positive T cells). And unlike conventional T cells, their TCR is very restricted, recognizing only glycolipid antigens presented by the MHC class 1-like molecule, CD1d. This interaction is important both in the developmental phase in the thymus (positive selection) and in the periphery in response to self and microbial lipids. Their TCR also recognizes conserved ligands much the way NK cells do in an innate immune response. They also secrete several cytokines, (e.g. IFN-γ, Il-4, Il-12, Il13 ) that participate in the adaptive immune response of both T and B cells, and thus are felt to serve an important role in the suppression of autoimmunity and tissue graft rejection. These cells represent less than 1% of the peripheral blood T cells, but are present in higher numbers in the liver sinusoids.